Scavenger receptor BI facilitates hepatic very low density lipoprotein production in mice

Abstract

The scavenger receptor BI (SR-BI) is well characterized for its ability to mediate selective uptake of cholesteryl ester from HDL particles into cells ( 1, 2 ). Consistent with this role, SR-BI expression is highest in the liver and in steroidogenic tissues ( 1 ). Recently, SR-BI has also been implicated in the catabolism of apolipoprotein (apo)B-containing lipoproteins such as chylomicrons and ␤ -VLDLs by hepatocytes ( 3-6 ). However, the fi rst study demonstrating that adenovirus-mediated SR-BI overexpression increases the HDL catabolic rate indicated that plasma levels of apoB-containing lipoproteins actually increased significantly over time, whereas HDL levels remained low ( 7 ). Interestingly, hepatic LDL receptor (LDLR) expression was unchanged in this study during the course of the experiment ( 7 ). These data suggest, in our view, the possibility that SR-BI might be involved in hepatic cholesterol secretion.Therefore, we hypothesized that SR-BI might facilitate hepatic VLDL production, providing a potential link between the HDL and the apoB-containing lipoprotein cholesterol pathways. Our data demonstrate that hepatic VLDL-triglyceride as well as VLDL-apoB production in vivo are decreased in SR-BI knockout mice and increased following SR-BI overexpression. The results of our study further indicate that HDL-derived cholesterol is to a certain extent resecreted by hepatocytes as a component of VLDL particles in a process dependent on SR-BI expression.Abstract Scavenger receptor BI (SR-BI) is a selective uptake receptor for HDL cholesterol but is also involved in the catabolism of apolipoprotein (apo)B-containing lipoproteins. However, plasma levels of apoB-containing lipoproteins increase following hepatic SR-BI overexpression, suggesting that SR-BI not solely mediates their catabolism. We therefore tested the hypothesis that hepatic SR-BI impacts on VLDL production. On day 7 following adenovirus (Ad)-mediated overexpression of SR-BI, VLDL-triglyceride and VLDL-apoB production rates were signifi cantly increased ( P < 0.001), whereas VLDL production was significantly lower in SR-BI knockout mice compared with controls ( P < 0.05). In mice injected with AdSR-BI, hepatic cholesterol content increased ( P < 0.001), microsomal triglyceride transfer protein activity was higher ( P < 0.01) and expression of sterol-regulatory element binding protein (SREBP)2 and its target genes was decreased ( P < 0.01). Conversely, in SR-BI knockout mice, microsomal triglyceride transfer protein activity was lower and expression of SREBP2 target genes was increased ( P < 0.01). Finally, we demonstrate in vitro in isolated primary hepatocytes as well as in vivo that cholesterol derived from HDL and taken up via SR-BI into the liver can be resecreted within VLDL. These data indicate that hepatic SR-BI expression is linked to VLDL production, and within liver, a metabolic shunt might exist that delivers HDL cholesterol, at least in part, to a pool from which cholesterol is mobilized for VLDL production. These results might have i...

CETP expression reverses the reconstituted HDL-induced increase in VLDL

“…Since each VLDL particle contains a single molecule of apoB, this indicates that rHDL infusion increases the lipidation of hepatic apoB rather than increasing the number of VLDL particles produced. Interestingly, it has been observed previously that increasing the fl ux of HDL to the liver by hepatic overexpression of scavenger receptor class B member 1 also increases the VLDL-TG production rate, and that HDL-derived cholesterol can be resecreted from the liver within VLDL particles ( 23 ). Therefore, we postulate that, in a similar manner, infusion of rHDL causes an increased net fl ux of lipids to the liver.…”

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

“…The decreased expression of SREBP-1c, MTTP, apoB, and CideB appears to favor the decreased hepatic VLDL production (supplementary Fig. 5) because these genes regulate VLDL production (32)(33)(34). Although both expression of FAS mRNA ( Fig.…”

The Membrane Lipid Phosphatidylcholine Is an Unexpected Source of Triacylglycerol in the Liver

“…This may indicate either that SR-BI is not involved in this process or that other pathways are compensating for the long term loss of SR-BI to enable adequate uptake of PC into the liver. On the other hand, in an acute model of adenoviral overexpression of SR-BI and thus increased hepatic uptake of HDL, hepatic TG levels increased 2-fold (41). This increase in TG might be due to increased uptake of HDL-associated PC into the liver followed by conversion of the PC into TG.…”